Components of Participating OrganizationsThis RFA is developed as part of the NIH-wide Genes and
Environment Initiative. All NIH Institutes and Centers participate in NIH-wide
initiatives. This RFA will be administered by NHGRI (http://www.genome.gov)
on behalf of the NIH (http://www.nih.gov).

October 13, 2006 - See Notice NOT-OD-07-006, This notice is to inform potential applicants that investigators from the NIH Intramural Research Program (IRP) will be eligible to participate in the NIH-wide Genes and Environment Initiative (GEI)..

The purpose of this funding
opportunity is to provide support for investigative groups to conduct genome-wide
association (GWA) genotyping and/or replication studies using data and samples
from human subjects on whom information is available for conditions/traits
of public health importance and relevant environmental exposures. It
includes support for sharing the samples and data and analyzing the
resulting data as part of the NIH-wide Genes and Environment Initiative
(GEI).

$5.5 million in FY 2007 funds
have been committed to fund applications in response to this RFA.

It is anticipated that 8-10 awards
will be made under this RFA. Awards are contingent on the
availability of funds and the submission of a sufficient number of
meritorious applications.

The total project period for an
application submitted in response to this RFA may not exceed two years.

This RFA will use the U01
Cooperative Agreement award mechanism.

Eligible organizations
include: For-profit organizations; non-profit organizations;
public or private institutions, such as universities, colleges, hospitals,
and laboratories; units of State and local governments; eligible agencies
of the Federal government; and domestic or foreign institutions.

Eligible principal investigators
include individuals with the skills, knowledge, and resources necessary to
carry out the proposed research. Individuals from underrepresented
racial and ethnic groups as well as individuals with disabilities are
always encouraged to apply for NIH support.

Applicants may submit more than
one application, provided they are scientifically distinct.

The purpose of this
funding opportunity is to provide support for investigative groups
(“Study Investigators”) to conduct genome-wide association (GWA)
genotyping and/or replication studies using data and samples from human
subjects on whom information is available for conditions/traits of public
health importance and relevant environmental exposures. It includes
support for sharing the samples and data and analyzing the resulting data as
part of the NIH-wide Genes and Environment Initiative (http://www.genome.gov/17516707).

The Genes and Environment
Initiative (GEI) is a four-year, NIH-wide program proposed in the
President’s FY2007 budget and currently awaiting Congressional approval.
If approved, the program will support efforts to identify major genetic susceptibility
factors for diseases of substantial public health impact and to develop
technologies for reliable and reproducible measurement of potentially causative
environmental exposures. It is being developed and implemented by an NIH-wide GEI
Coordinating Committee, administratively led by the National Human Genome
Research Institute (NHGRI) and the National Institute of Environmental Health
Sciences (NIEHS).

GEI is intended to be a
multi-component program involving several related solicitations. A major
component (GEI-GWA) will support genome-wide association studies (GWAS), either
in an initial discovery phase (assaying single nucleotide polymorphisms, or
SNPs, to capture at least 80% of human genomic variation), or in a replication
phase (assaying a subset of the most strongly associated SNPs or other genetic
variants in one or more additional groups of subjects), or both. Other GEI
genetics components under consideration for future solicitations include
development of data analytic methods, further replication and fine mapping
studies, sequencing, functional studies, database development, and clinical
translation. As these latter activities depend on availability of robust
findings from high-throughput GWA genotyping, the production and analysis of
those data will be the focus of this first component of GEI.

Recognizing that chronic
diseases are likely due to environmental and behavioral factors interacting
with genetic predisposition, GEI also includes a substantial environmental
component devoted to developing and field testing new technologies for
assessing such exposures. The potential for applying these technologies
(particularly those suitable for use on stored biospecimens) in population
samples selected through GEI for GWA studies will also be examined. Other GEI
exposure biology components under consideration include development of environmental
sensors for measurement of toxins, dietary intake, and physical activity;
biologic markers of response, including oxidative stress, epigenetics, and DNA damage;
and psychosocial stressors.

The value of the existing
epidemiologic data in these population samples for investigation of
gene-environment interactions will be increased substantially by the addition
of GWA genotyping. To ensure that the maximal scientific benefit is derived
from this significant public investment, genotype data produced by GEI-GWA will
be combined with phenotype and exposure data shared by the Study Investigators,
according to their data sharing plans, and will be made rapidly and widely
available for research use, consistent with evolving NIH policies on data
sharing in GWAS (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html).

Background

Genome-wide association studies
have emerged as a powerful new tool for identifying genetic variants related to
common, complex diseases such as age-related macular degeneration and diabetes.
Diseases such as cancer, hypertension, osteoporosis, and stroke, which have
generally not yielded genetic variants of large population impact in family
linkage studies, may be amenable to study through interrogation of common
genetic variation as defined by the International HapMap Project and related
programs. Identification of disease-related genes can now be accelerated by
systematically genotyping large collections of human subjects who have already
been carefully characterized for a wide variety of common diseases and traits.
Many large population studies have been supported by NIH to collect DNA samples
and perform extensive and often repeated measurements of physical
characteristics, disease risk factors and outcomes, and environmental
exposures. These samples are now well suited for application of HapMap-based, genome-wide
association technology, either as initial “discovery” studies interrogating
the entire genome, or as follow-up “replication” studies to confirm
initial results with additional population samples.

Interrogation of the
genome with hundreds of thousands of genotype assays remains costly and has the
potential for producing many false positive associations, even at the most
stringent levels of type I error correction. This may best be dealt with by
using a multi-stage design, in which very large numbers of markers are typed in
a subset of a given population sample, and those most strongly associated with
the trait of interest are subsequently typed in the remainder of the sample.
Various strategies have been proposed for analyzing the resulting data, such as
separate, independent analyses or a joint analytic scheme. Replication of
findings in an independent study sample, collected under different conditions
or by different investigators, has been suggested as a requirement for
publication of GWAS findings. Strategies for reducing “false
discoveries” and identifying true positives in a rapid and cost-effective
way are currently the subject of intense research. Other analytic issues, such
as identification of gene-gene and gene-environment interactions,
interpretation of resequencing data, and adjustment for population structure,
are also subjects of active investigation, which will be further stimulated by
the wide availability of GWA data.

Genotyping platforms are
also continuing to evolve, with ever-larger numbers of SNPs available for
typing at progressively lower costs. A variety of approaches has been proposed
for selecting a set of “tag” SNPs to capture the majority of
inter-individual genomic variation for use in GWA discovery scans, and for
determining which subsets of associated markers should be followed up in
replication studies. SNP selection can also be limited by genotyping
platforms, and generally becomes less flexible as the number of SNPs to be assayed
increases. Patterns of linkage disequilibrium (LD) and founder effects also
influence the selection of markers, with larger numbers needed for populations
with lower levels of LD, such as those of recent African ancestry, and
potentially different markers needed for those with strong founder or selection
effects. Technologies are also under development for assaying genetic markers
other than SNPs, such as small insertions/deletions and copy number variants; these
may be incorporated into genotyping platforms in the four-year course of GEI. Technologic
developments are anticipated to continue for the duration of GEI, and will
require the program to remain flexible in adapting to evolving technology.
Indeed, GEI-supported research can be expected to contribute positively to this
developmental process.

Although traditional
methods to assess exposure can accurately determine the concentration of a
variety of toxins in the environment or in human biospecimens, these methods
fall short of accurately determining the biological response to exposures.
Evidence suggests that the biological response to the exposure, rather than
simply the exposure, is more tightly related to the ultimate impact on human
health. For the purposes of GEI, environmental exposure refers to chemical
toxicants such as metals and solvents, and biological agents such as toxins
released from mold and bacteria, that are contaminants of the natural
environment of air, water, and soil. It also encompasses lifestyle factors such
as diet and physical activity which contribute to and modulate the biological
response to these environmental agents. Family, social and cultural influences
that may modify the pathophysiologic responses to environmental exposures will
be considered to the extent that they can be measured in biological assays. It
is fully expected that the technological achievements supported by GEI will
result in assays providing biological “fingerprints” of prior
exposure to environmental agents and lifestyle choices. These improved exposure
measures can be linked to GWA data to determine their relationships to genomic
variants, as well as their potential for modifying the associations of these
variants with disease.

Scientific Knowledge to
be Achieved

The NIH-wide Genes and
Environment Initiative (GEI) has the long-range goal of determining the
etiology of common diseases by focusing on genetic and environmental factors
that increase the risk of these diseases, and the interaction among these
factors. GEI will provide valuable scientific contributions to health
disparities research by collecting and analyzing genotype, phenotype, and
exposure data, while simultaneously measuring other factors within disease
subgroups (e.g., race, ethnicity, behaviors, geography, genetic backgrounds,
exposures and social environments) that may lead to differential health
outcomes.

The GWA component of GEI (GEI-GWA)
will identify genetic variants associated with complex diseases and traits in
initial genome-wide discovery studies and, as feasible and appropriate, will
reduce false positive associations through suitable replication strategies. It
will also identify variations in gene-trait associations related to
environmental exposures, to distinguish population subgroups potentially
susceptible to these exposures. The GWA component will address potential
pathways to disparities in health outcomes, including but not limited to
environmental exposures, genetic variations and/or other underlying biological,
race/ethnic, social, and familial factors, to the extent feasible with the data
available in existing studies.

Objectives of this
Research Program

This RFA will support Study
Investigators to add genome-wide association studies to existing studies of
diseases and traits of substantial public health impact; study designs may include
case-control, population, cohort, clinical, or family studies or clinical
trials. Study Investigators may seek to identify associations of genetic
variants with the presence of a particular disease or discrete trait (such as
colorectal cancer or anxiety disorder), or with levels of a quantitative trait
(such as cognitive function or visual acuity) and may examine interactions
among genetic and environmental factors, susceptibility to multiple conditions,
or associations of genes with disease risk factors, disease incidence, or
therapeutic responsiveness. A diversity of participant populations regarding
age, sex, race/ethnicity, and environmental exposures will be supported under
this RFA.

Investigators are
expected to have access to data and sources of DNA from an existing study population(s)
of sufficient size to adequately test the proposed hypotheses at the time that
the application is submitted. Funding will be provided to support sharing
phenotype and exposure data with a central database, and DNA samples (or biospecimens
for DNA extraction) with a central genotyping facility, as well as for
collaborative activities (standardization or harmonization of phenotypes where
possible, assessment of data quality, development of analytic strategies, etc.)
and data analysis. No recruitment or sample acquisition will be supported
by this RFA. Two accompanying solicitations: HG-06-014, Genome-wide Association
Studies in the Genes and Environment Initiative – Genotyping Facilities,
and HG-06-032, Genome-wide Association Studies in the Genes and Environment
Initiative – Coordinating Center, will support the genotyping and
coordination activities of the program. Overall, NIH anticipates funding 12-15
studies: 8-10 studies under HG-06-033, and roughly six studies under
solicitations planned for release in FY08 and FY09.

Each application should
clearly define the public health significance and genetic complexity of the
trait(s) proposed for study, the need for a genome-wide association study (initial
discovery phase or replication phase, as proposed in the application), the
strength of the evidence for a genetic component for the trait, the anticipated
size of a detectable genetic effect, and the power of the proposed sample to
detect it. Choice of population and study design should be dictated and
justified by the scientific questions addressed in each application, such as
the epidemiology and biology of the disease or trait. Adequacy of
informed consent for GWA studies and for controlled but widespread data access
(described below) should be clearly described, along with any restrictions on
research use of the data. Each application should also clearly describe
the types, quality and completeness of the available phenotype and environmental
exposure data, the strength of evidence for an environmental component for the
trait, the anticipated size of the environmental effect, and the power to
detect it. This RFA may support a variety of study designs derived from
existing population, family and clinical studies including, but not limited to,
case-control, cohort, case-cohort, family-based studies, and clinical trials.
Sources of, inclusion and exclusion criteria for, and generalizability of the
population sample (whether cohort, case-control, etc) should be clearly
described. Any potential biases in subject selection (including, if
applicable, controls as well as cases) and approaches for minimizing these
biases should be described. Applicants may provide suggestions on choice
of genotyping platform, number of genetic markers and method of choosing genetic
markers with respect to the proposed study population, design, analytic plan
and biology and epidemiology of the disease or phenotype. Final decisions on
genotyping platform and marker selection will be made in collaboration with the
GEI-GWA Steering Committee and the GEI-GWA Project Scientist.

Applicants should
describe any previous genotyping carried out on the samples to be submitted,
particularly whether any genome-wide linkage or association studies have been
carried out and how those data will be incorporated into the GWA analyses
proposed in this application. A strong justification should be
provided for additional genotyping beyond what has already been performed, and
a clear indication given of whether results of prior genotyping efforts will be
included in the dataset submitted to NCBI (see below). Applicants should
also describe any known GWA studies by other investigators of the same disease
or trait as proposed in their application, and explain how GEI genotyping of
the proposed sample set will complement these efforts.

Phenotypes selected for GWA
analysis should be unambiguously defined using standardized and validated
methods where possible. Standardized and validated methods should also be
described for the environmental exposures and other covariates proposed for
inclusion in analyses. Completeness and validity of data on important
covariates and environmental exposures, and the approach for using these data
in genotype-phenotype association analyses, should be described.

Exposure data to be
included in GWA analysis should be clearly described and may include: questionnaire-
or interview-based information about environmental exposure to chemicals and
biological toxins, diet, and physical activity; environmental monitoring data
derived from analysis of air (particulates, gases), water, soil, sediment, or
food samples collected in the personal, home, school or general environment; or
previously collected body burden estimates. It is highly desirable to
have available biospecimens (such as whole blood or serum, urine, hair, or RNA)
for future analysis when new methods and technology for exposure assessment
become available. Such testing will be done under a separate GEI
solicitation. Applicants should describe the types of stored biospecimens
from participants proposed for GWA analysis and the availability of these
specimens for future use.

A detailed analytic plan
should address issues related to the large amount of GWA data to be generated
such as multiple testing and assessing complex interactions (e.g., gene by
gene, gene by environment including gene by drug, pleiotropy, epistasis). The
potential impact of population ancestry/history and stratification on GWA
analyses should be discussed regardless of the population chosen for study, and
means for minimizing the effects of population stratification proposed. The
analytic plan should detail methods to address false positives and adjust for
multiple testing.

Applicants should
describe their plans for replication and follow-up studies if an association is
found, including current availability of a suitable replication sample.
Applicants may propose samples for initial GWA (discovery) genotyping, for
replication testing of a subset of associated markers from a prior GWA
discovery study, or a combination of both. Plans for replication of GEI-GWA
findings should be described in detail, whether proposed for support within GEI-GWA
or not. Such plans should include strategies to minimize false negative
as well as false positive associations, and should specify and justify the size
and number of the replication phases and the criteria for retaining candidate
markers from one stage to the next. Such criteria may include, for
example, the anticipation of a few relatively strong genetic determinants vs.
many relatively weak ones, and should be supported by available data or
literature. Applicants should describe the similarity (or differences, if
appropriate) between replication phases in terms of disease definition,
populations, covariates, environmental exposures, study designs, and
recommended genotyping technology, and the approach for dealing with multiple
subphenotypes or extreme phenotypes, if applicable.

At some point in this
overall analytic process, candidate markers of great interest (as defined by consistency
of findings, magnitude of effect, biologic credibility, etc) will emerge and
should be followed up by efforts to genotype with greater density in the areas
surrounding the particular marker. Applicants should describe plans for such
“fine mapping,” if appropriate, in their replication strategies, as
an option to be considered once the scope of fine mapping is better defined.
Such plans should include criteria for when to begin fine-mapping efforts, how
to select candidates for these efforts and/or functional analysis of candidate
variants, and when to move from fine mapping with existing markers to direct resequencing
efforts. These plans will likely be the subject of much discussion within the GEI-GWA
collaborative group, which will work together to develop a consensus strategy
for such studies.

Applicants should
describe their plans for ensuring the security and integrity of GEI-GWA data
and for maintaining the privacy of study participants.

Program Organization

The GEI-GWA program is
part of the larger GEI program, which will include additional initiatives in
genetics and exposure biology. The GEI-GWA program includes awards for Study
Investigators (this RFA), a Coordinating Center (HG-06-032), and Genotyping
Facilities (HG-06-014). The awards funded under all three GEI-GWA RFAs
will be cooperative agreements (see Section VI.2.A. Cooperative Agreement Terms
and Conditions of Award).

Close interaction with
the other components of the GEI-GWA program, including the NIH, will be
required to develop appropriate strategies and tools to design, perform, and
analyze genome-wide association studies. The awardees will meet as a GEI-GWA Steering
Committee, which will include representatives from the Coordinating Center, Genotyping Facilities, Study Investigators, and NIH, three times per year and monthly
on conference calls as needed to share information on data resources,
methodologies, analytical tools, as well as data and preliminary results. Subcommittees
and working groups may be established, such as a Genotyping group or an
Analysis group. Key co-investigators, and pre- and postdoctoral trainees,
in addition to the PIs, are eligible to attend these meetings. PIs are
encouraged to include investigators and trainees who are members of
under-represented minority groups and those from different but related
disciplines such as computational biology, social sciences, public health, and
translational research where appropriate. The cost of 3-4 persons to attend
these meetings, as well as the costs associated with monthly conference calls,
should be included in the proposed research budget. All unidentified,
individual-level phenotypic, environmental exposure, and genotypic data
proposed for GEI-GWA analysis will be made available to the scientific
community through a controlled access process managed by NIH. Summary data
and other non-identifying information such as study protocols, descriptions,
and publications will be made openly available through a public web site and
publication in the scientific literature.

This initiative will not
support the recruitment of human subjects, collection of human samples,
collection of medical or phenotype data, or studies using animal models.
Applications that include recruitment of human subjects, collection of human
samples, collection of medical or phenotype data, and studies using animal
models will be considered non-responsive and returned to the applicant.

Proof of
appropriate informed consent for the previously collected data, or a plan for
reconsent, should be provided at the time of application submission. Only
applications describing protection of participants’ privacy and
confidentiality will be considered.

Section
II. Award Information

1. Mechanism(s) of Support

This funding opportunity
will use theNIH
U01 Cooperative Agreementaward mechanisms.

As an
applicant, you will be solely responsible for planning, directing, and
executing the proposed project.

This funding opportunity
uses the just-in-time budget concepts. It also uses the non-modular budget
format described in the PHS 398 application instructions (see https://grants.nih.gov/grants/funding/phs398/phs398.html).
A detailed categorical budget for the "Initial Budget Period" and the
"Entire Proposed Period of Support" is to be submitted with the
application.

Applications from foreign (non-U.S.) institutions
submitted using the PHS 398: Follow the
NON-MODULAR FORMAT instructions and submit Form Page 4 and Form Page 5. Do not
complete or submit the Modular Budget Format Page.

The NIHU01is a cooperative agreement
award mechanism. In the cooperative agreement mechanism, the Principal
Investigator retains the primary responsibility and dominant role for planning,
directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the Principal Investigator, as
described under the Section VI. 2. Administrative
Requirements, "Cooperative Agreement Terms and Conditions of
Award".

NIH
plans to reissue this RFA in FY08, and potentially in FY09, to fund roughly six
additional GWA studies.

2. Funds Available

The NIH expects to award
approximately $10,000,000 (total costs) over a two-year period through
this announcement ($5,500,000 in FY2007, $4,500,000 in FY2008).

The NIH anticipates funding 8-10
new awards in response to this announcement. NIH plans to reissue this RFA
in FY08, and potentially in FY09, to fund roughly six additional studies.

An applicant may request a
project period of up to two years.

The expected amount for each
award is approximately $750,000 in direct costs for the full project period.

The anticipated start date is July 1, 2007 and the period of performance is July 1, 2007 to June 30, 2009.

Because
the nature and scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award will
also vary. Although the financial plans of the IC(s) provide support for this
program, awards pursuant to this funding opportunity are contingent upon the
availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and
administrative costs requested by consortium participants are not included in
the direct cost limitation, see NOT-OD-05-004.

Section
III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit
applications if your organization has any of the following characteristics:

For-profit organizations

Non-profit organizations

Public or private institutions,
such as universities, colleges, hospitals, and laboratories

Units of State government

Units of local government

Eligible agencies of the Federal
government

Foreign Institutions

Domestic Institutions

Faith-based or community-based
organizations

1.B.
Eligible Individuals Any individual with the
skills, knowledge, and resources necessary to carry out the proposed research
is invited to work with their institution to develop an application for
support. Individuals from underrepresented racial and ethnic groups as well as
individuals with disabilities are always encouraged to apply for NIH support.

Applications must be
prepared using the most current PHS 398 research grant application instructions
and forms. Applications must have a D&B Data Universal Numbering System
(DUNS) number as the universal identifier when applying for Federal grants or
cooperative agreements. The D&B number can be obtained by calling (866)
705-5711 or through the web site at http://www.dnb.com/us/.
The D&B number should be entered on line 11 of the face page of the PHS 398
form.

The title and number of this funding opportunity must
be typed on line 2 of the face page of the application form and the YES box
must be checked.

Foreign Organizations

Several special provisions apply to applications
submitted by foreign organizations:

Charge back of customs and import fees is not allowed.

Format: every effort should be made to comply with the
format specifications, which are based upon a standard US paper size of 8.5" x 11."

Applications
from foreign (non-U.S.) institutions submitted using the PHS 398: Follow the NON-MODULAR FORMAT
instructions and submit Form Page 4 and Form Page 5. Do not complete or submit
the Modular Budget Format Page.

Proposed
research should provide special opportunities for furthering research programs
through the use of unusual talent, resources, populations, or environmental
conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

3. Submission Dates and Times

Applications must be received
on or before the receipt date described below (Section
IV.3.A). Submission times N/A.

Prospective applicants
are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed research

Name, address, and telephone number of the Principal
Investigator

Names of other key personnel

Participating institutions

Number and title of this funding opportunity

Although a letter of
intent is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows IC staff to
estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed
at the beginning of this document.

Applications must be
prepared using the research grant applications found in the PHS 398
instructions for preparing a research grant application. Submit a signed,
typewritten original of the application, including the checklist, andthreesigned photocopies in one
package to:

Using the RFA Label: The RFA label available in
the PHS 398 application instructions must be affixed to the bottom of the face
page of the application. Type the RFA number on the label. Failure to use this
label could result in delayed processing of the application such that it may
not reach the review committee in time for review. In addition, the RFA title
and number must be typed on line 2 of the face page of the application form and
the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application
Processing

Applications must be received on or before the
application receipt date(s) described above (Section IV.3.A.).
If an application is received after that date, it will be returned to the
applicant without review. Upon receipt, applications will be evaluated for
completeness by the CSR and responsiveness by theNIH.Incomplete and non-responsive
applications will not be reviewed.

The NIH will not accept
any application in response to this funding opportunity that is essentially the
same as one currently pending initial review, unless the applicant withdraws
the pending application. However, when a previously unfunded application,
originally submitted as an investigator-initiated application, is to be
submitted in response to a funding opportunity, it is to be prepared as a NEW
application. That is, the application for the funding opportunity must not
include an Introduction describing the changes and improvements made, and the
text must not be marked to indicate the changes from the previous unfunded
version of the application.

All NIH awards are
subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement. The Grants Policy Statement can
be found at https://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its
own risk and without NIH prior approval, incur obligations and expenditures to
cover costs up to 90 days before the beginning date of the initial budget
period of a new or competing continuation award if such costs: are necessary to
conduct the project, and would be allowable under the grant, if awarded,
without NIH prior approval. If specific expenditures would otherwise require
prior approval, the grantee must obtain NIH approval before incurring the cost.
NIH prior approval is required for any costs to be incurred more than 90 days before
the beginning date of the initial budget period of a new or competing
continuation award.

The incurrence of pre-award costs in anticipation of a
competing or non-competing award imposes no obligation on NIH either to make
the award or to increase the amount of the approved budget if an award is made
for less than the amount anticipated and is inadequate to cover the pre-award
costs incurred. NIH expects the grantee to be fully aware that pre-award costs
result in borrowing against future support and that such borrowing must not
impair the grantee's ability to accomplish the project objectives in the
approved time frame or in any way adversely affect the conduct of the project.
See NIH Grants Policy Statement https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements

Special Application Requirements for Study Investigators

Applicants must address
the following when preparing applications in response to this RFA. Items
A–D in the application (Specific Aims, Background and Significance,
Preliminary Studies, and Research Design and Methods) should not exceed 25
pages.

Applicants are expected
to document access to existing DNA specimens and phenotypic data from an
existing human population-, clinic-, or family-based study. Consistent
with the data sharing plan, samples should be available for sharing with GEI-GWA
Genotyping Facilities within one month of award. Applicants should describe
all relevant phenotypic and environmental exposure measures from the
study. Applicants should provide strong justification for the choice of
population and sampling design.

Human Subjects (as
part of item E in the application)

The applicant must address
human subjects issues, including sharing phenotypic and genetic data from
individual participants with the broad scientific community.

Applicants are expected
to demonstrate that the informed consent for the existing study population(s)
allows for the genetic study proposed and sharing phenotypic and genetic data
with the broad scientific community. If this is not the case, a plan should
be proposed for obtaining reconsent including IRB approval, or an IRB waiver of
reconsent for data sharing, and a specific budget for reconsent should be
provided. Plans for reconsent, including consent forms, must be approved
by the NHGRI Program Director prior to implementation. Any restrictions
on data use (such as limitations to a specific disease or condition or to
non-commercial investigators) should be clearly described. Restrictions
on data use will be considered in the selection process. Copies of the applicable
existing informed consent forms should be included in the grant application.

Applications that include
recruitment of human subjects, collection of human samples, and/or collection
of phenotypic or medical data will be considered non-responsive and returned to
the applicant.

To be considered
responsive, applicants must submit summary phenotypic, exposure, and covariate
data on subjects proposed for GWA genotyping to the National Center for Biotechnology Information (NCBI) prior to or on this RFA’s application receipt
date (“meta-data” and summary statistics, not individual-level
data; see Requirements for Data Description at http://www.ncbi.nlm.nih.gov/WGA/programs/GEI/). Applicants should contact
NCBI at wga@ncbi.nlm.nih.gov well
before the submission deadline to discuss the format and requirements for this
transfer. NCBI will provide an account name and password and discuss the
files and formats that the applicant plans to upload. Once an agreement is
reached between the applicant and NCBI, the files must be uploaded to the
secure FTP site at NCBI before the application submission deadline. All information
provided during the application process will be treated as confidential, in the
same manner as all other information in a grant application. It will be placed
in a secure NCBI-managed environment with access limited to NIH staff directly
involved in the technical assessment component of the GEI-GWA program. Information
in this environment will be backed up to a private internal store for this program
and will be distributed only as necessary to complete the review process.
Reviewers may receive copies of the information for consideration in the
initial peer review. Technical evaluation of the dataset by NCBI will
include assessment of: extent of human curation needed to integrate the
documentation with the phenotype data; certainty with which NCBI can interpret the
meaning of the variables provided, with or without reference to supplemental
documentation; frequency and distribution of trait measures that have been
recoded and quality of documentation to define those values; extent of missing
and out-of-range values; and clarity of case and control definitions. The
outcome of the NCBI technical evaluation will be provided to reviewers for consideration
in the initial peer review. Applicants are responsible for removing any
potentially identifying information prior to submission of the information.

Applicants
who are being considered for an award under this RFA will be expected to send
individual-level data to NCBI within two weeks of receiving notice that they are
being considered for an award. Award is contingent on consistency of the
dataset with the “meta-data” provided as part of the application,
as assessed by NCBI. Such applicants will also be expected to submit a
randomly selected sample of about 100 DNA specimens, or specimens from which
DNA will be extracted, for assessment of DNA quantity and quality, within two
weeks of receiving notice that they are being considered. Award is contingent
on acceptable DNA quantity and quality as judged by the assigned Genotyping
Facility. If an award is not made, individual-level data will be treated
as confidential, in the same manner and under retention policies as all other
information in a grant application; they will not become part of the GEI-GWA
database and will not be shared. If an award is made, the
individual-level data will become part of the GEI-GWA database and will be made
available as described under “Plans for Sharing Research Data.”

Applicants
being considered for an award are expected to have in place appropriate
Institutional Review Board (IRB) and any other required approvals for sharing
individual-level data with NIH and submitting DNA specimens, or specimens
from which DNA will be extracted, to an NIH-designated central genotyping
facility. Applicants being considered for an award will also be required
to document IRB approval for submitting individual-level phenotype and exposure
data and genotyping results to a shared data resource as described under
“Plans for Sharing Research Data,” or IRB approval for a reconsent
process.

Applicants should describe
prior experience in working as part of a research consortium or other
collaborative activities to meet individual study and collaborative goals.

Plan for Sharing Research
Data All applicants must
include a plan for sharing research data in their application. The
reasonableness of the data sharing plan will be assessed by the reviewers.
However, reviewers will not factor the proposed data sharing plan into the
determination of scientific merit or the priority score.

The applicant should
provide specific plans for data sharing and data release in the application and
indicate his/her willingness to abide by the current NIH data release policy,
as modified by the public input process described below. See Request for
Information: Proposed Policy for Sharing of Data obtained in NIH supported or
conducted Genome-Wide Association Studies (GWAS); https://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html. It is expected that, after
public input, NIH will establish a common policy for data release, publication,
and intellectual property for GWA studies and that all participants will agree
to abide by that policy.

The NIH is committed to
the principle of rapid data release to the scientific community. This
principle was initially implemented during the Human Genome Project and has
been recognized as leading to one of the most effective ways of promoting the
use of the genome sequence data to advance scientific knowledge. At a
meeting in Ft. Lauderdale, FL that was co-sponsored by the Wellcome Trust and
NHGRI in January 2003, the concept of rapid data release by genomic sequence
data producers was reaffirmed, and the attendees strongly recommended applying
the practice to other types of data produced by “community resource
projects”. The attendees recognized, however, that different
issues, particularly with respect to data validation, would be involved in the
development of appropriate release practices for different types of data.
Since they also recognized that sustaining the practice of rapid,
prepublication data release by community resources requires that the interests
of all involved - including the data producers, data users, and funding
agencies - be addressed, they emphasized the need to develop a tripartite
system of responsibility. The report from the Ft. Lauderdale meeting can be
found on the Wellcome Trust website at:
http://www.wellcome.ac.uk/doc_wtd003208.html.

The NIH has identified
the GWA component of GEI as a community resource project. As such, the program
aims to function openly by making all data available to the scientific
community in a timely manner prior to publication, with suitable restrictions
for protection of human research subjects. The NIH is committed to
creating a resource founded on the principle of no-cost, rapid, and complete
release of GEI-GWA Project Datasets for use by investigators throughout the
global scientific community who, along with their institutions, certify their
agreement with GEI policies (“Approved Users”). All
participants in GEI-GWA (Study Investigators, Coordinating Center, Genotyping Facilities, NIH, and Approved Users) are expected to promote the GEI-GWA
policies on data access, publication, and intellectual property summarized
below, and describe their methods for doing so in the application. NIH,
in collaboration with the GEI-GWA Steering Committee, will establish mechanisms
to monitor data use in agreement with GEI policies.

The NIH, in consultation
with the GEI-GWA Steering Committee, will make all final decisions concerning
GEI-GWA policies. All GEI-GWA policies are subject to change by the NIH
as deemed necessary to sustain program principles and priorities, or to ensure
the highest standards for responsible research conduct within GEI operating
procedures. Access to the GEI-GWA Database, managed by NCBI, will be
overseen by the NIH in accordance with U.S. Government rules and policies.

Data Access: The GEI-GWA Database
will comprise two sections: open access and controlled access. Information
describing the phenotype data, such as the variables measured and protocols
used to collect the data and samples, but not the phenotype dataset itself,
will be made available in the open access part of the GEI-GWA Database. GEI-GWA
Project Datasets (genotype data as well as genotype-phenotype datasets along
with pre-computed analyses of them) will be available through the controlled
access section of the GEI-GWA Database. Although all GEI-GWA Project
Datasets from funded applications will be made available through the controlled
access section of the GEI-GWA Database, the NIH does not intend the GEI-GWA
Database to become the exclusive source of GEI-GWA Project Datasets.

The genotype data
generated for each sample, plus unidentified phenotype and exposure data, will
be deposited in a controlled access section of the GEI-GWA Database as soon as
both the phenotype and exposure data submitted by Study Investigators and the
GEI-GWA genotype data have passed appropriate data quality assessments; quality
standards will be developed by the GEI-GWA Steering Committee in collaboration
with NCBI and NHGRI. Simple, unadjusted genotype-phenotype associations (“pre-computes”)
will be calculated and posted in the GEI-GWA Database, along with a listing of
all variants known to be in strong linkage disequilibrium with variants showing
significant association with a phenotype or trait. Other analyses, such
as annotated information on genes and genomic features in identified regions of
interest, may be provided as well.

Access to GEI-GWA Project
Datasets through the GEI-GWA Database will be provided for research purposes
through a Data Access Committee (DAC). To become an Approved User, investigators
seeking data from the controlled access section of the GEI-GWA Database should
submit a Data Use Certification that is co-signed by the designated
Institutional Official, for approval by the GEI-GWA DAC. The Data Use
Certification will include a brief description of the proposed research use of
the requested GEI-GWA Project Dataset(s). As part of the Data Use
Certification, investigators will stipulate that they will: use the data only
for the approved research use; protect data confidentiality; follow all
applicable laws and any local institutional policies and procedures for
handling GEI-GWA Project data; not attempt to identify individual participants
from whom data within a dataset were obtained; not sell or share any of the
data elements from datasets obtained from the GEI-GWA Database with third
parties, other than sharing with their own research staff who have agreed to
GEI policies; and provide annual progress reports on research. Access to
a GEI-GWA Project Dataset through the GEI-GWA Database will be approved by the
DAC following: completion of the Data Use Certification; and confirmation that
the proposed research use is consistent with any constraints identified by the
Study Investigators who submitted the data to the GEI-GWA Database.

The terms and conditions
governing data access for research use of GEI-GWA Project Datasets for GEI-supported
investigators and NIH will be identical to those for any other member of the
scientific community seeking to become an Approved User, except that a Study
Investigator may be able to identify individual participants in her or his own
study and may share her or his own data with third parties at her or his
discretion. All Submitted Samples provided to GEI-GWA Genotyping
Facilities by Study Investigators for GEI-GWA use will be returned or destroyed
following the completion of the specified genotyping services according to the
procedures set by the contributing study site.

Publication Policy: Beginning
on the date that a GEI-GWA Project Dataset is released for distribution through
the GEI-GWA Database, there will be a period of nine months during which Study
Investigators retain the exclusive right to submit publications developed with
the data and samples they contributed. During this nine-month period of
exclusivity, Approved Users will have access to data in the GEI-GWA Database,
but will agree not to submit for publication any results or analyses derived
from the use of any GEI-GWA Project Dataset within that period without consent
of the Study Investigator. Submission of publications using GEI-GWA
genotype data only that may be available through dbSNP is permissible during
this period. Study Investigators will be encouraged to shorten the period
of exclusivity at their own discretion. NHGRI may request a shorter
period of exclusivity. The NIH expects that, in all resulting oral or
written publications, disclosures, or publications, all investigators who
access GEI-GWA Project Datasets will acknowledge the Study Investigator(s) who
conducted the original study and the funding organization(s) that supported the
work.

Intellectual Property
Policy: The NIH expects that GEI-supported data and conclusions derived directly
there from will remain freely available, without any licensing requirements,
for uses such as, but not necessarily limited to, markers for developing assays
and guides for identifying new potential targets for drugs, therapeutics, and
diagnostics. The intent is to discourage the use of patents that would
prevent use of or block access to any genotype-phenotype data developed with
GEI support. The NIH encourages broad use of GEI-GWA Project Datasets that
is consistent with a responsible approach to management of intellectual
property derived from downstream discoveries as outlined in NIH’s Best
Practices for the Licensing of Genomic Inventions and the NIH Research Tools
Policy (https://grants.nih.gov/grants/intell-property_64FR72090.pdf).

The filing of patent
applications and/or the enforcement of resultant patents in a manner that might
restrict use of the GEI-GWA Project Datasets and the GEI-GWA Database could
substantially diminish the utilization of information and the potential public
benefit they could provide. Approved Users and GEI-supported investigators, and
their institutions, should acknowledge the GEI-GWA IP Policy, the goal of which
is to ensure the greatest possible public benefit from GEI-GWA Project Datasets.

The adequacy of the resources sharing plan and any
related data sharing plans will be considered by Program staff of the funding
organization when making recommendations about funding applications. The
effectiveness of the resource sharing will be evaluated as part of the
administrative review of each non-competing Grant Progress Report (PHS 2590, https://grants.nih.gov/grants/funding/2590/2590.htm).
See Section VI.3. Reporting.

As the GWA component of GEI is
a community resource project, NIH expects that not only data, but also
resources generated during the course of the program, such as analytic methods
and data standards, will be made rapidly available to the research community
and that sharing plans should follow the same principles and spirit as the
rapid data release policy. The applicant should provide specific plans
for resource sharing and distribution in the application.

Section
V. Application Review Information

1. Criteria

The following will be
considered in making funding decisions:

Scientific
merit of the proposed project as determined by peer review

Availability
of funds (requires approval of GEI funding in the President’s
FY2007 budget)

Relevance of program priorities

Synergy with other funded
projects

Additional
criteria for award will include:

Public health
significance of disease/trait to be studied

Programmatic
balance among diseases

Appropriate
gender and race/ethnic representation

Quality and ease
of use of the data set as assessed by NCBI

Willingness of
PI and major co-investigators to collaborate with the NIH and with other Study
Investigators, Genotyping Facilities, and the Coordinating Center participating in the GEI-GWA program

Quality and
quantity of DNA available for GWA genotyping as assessed by an NIH-selected
genotyping facility

The
awardee must agree to the “Cooperative Agreement Terms and Conditions of
Award” in Section VI.2.A. “Award Administration Information.”

2. Review and Selection Process

Applications that are
complete and responsive to the RFA will be evaluated for scientific and
technical merit by an appropriate peer review group convened by NHGRI in accordance with the review
criteria stated below.

As part of the initial
merit review, all applications will:

Be technically evaluated by staff of the National Center for Biotechnology Information (NCBI), National Library of Medicine for
responsiveness, as described above in Section IV.6. Other Submission
Requirements. The outcome of NCBI’s technical evaluation for
responsiveness will be provided to the peer review group.

Undergo a
selection process in which only those applications deemed to have the
highest scientific merit, generally the top half of applications under
review, will be discussed and assigned a priority score.

Receive a
written critique.

Receive a
second level of review by the National Advisory Council for Human Genome
Research.

The
goals of NIH supported research are to advance our understanding of biological
systems, to improve the control of disease, and to enhance health. In their
written critiques, reviewers will be asked to comment on each of the following
criteria in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application. Note that an application does not need to be
strong in all categories to be judged likely to have major scientific impact
and thus deserve a high priority score. For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward.

Significance: Does this study address an
important problem? If the aims of the application are achieved, how will scientific
knowledge or clinical practice be advanced? What will be the effect of these
studies on the concepts, methods, technologies, treatments, services, or
preventative interventions that drive this field?Does the application address a
significant and genetically complex trait and demonstrate the need for a genome-wide
association study for this trait?

Approach: Are the conceptual or
clinical framework, design, methods, and analyses adequately developed, well
integrated, well reasoned, and appropriate to the aims of the project? Does the
applicant acknowledge potential problem areas and consider alternative tactics? Are the study
design and population chosen appropriate for the aims proposed? Are the
proposed plans to share data in a timely manner adequate? Have the
sources and generalizability of study subjects, particularly the controls (if
applicable) been clearly described, have any potential biases in subject
selection been identified, and are the applicants’ approaches for
minimizing these biases appropriate? Are the phenotype and exposure
measures to be included in the GEI datasets of sufficient quality and
completeness to provide maximal scientific value from the addition of GWA
genotyping?

Innovation: Is the project original and
innovative? For example: Does the project challenge existing paradigms or
clinical practice; address an innovative hypothesis or critical barrier to
progress in the field? Does the project develop or employ novel concepts,
approaches, methodologies, tools, or technologies for this area?What advantages does this data set
offer over others in terms of strategies for data management and data
analysis? What advantages does it offer for replication studies and
follow-up studies to identify causative genetic variants and develop
diagnostic, preventive, or therapeutic strategies? What is the richness
of the dataset for future studies that may be based on other phenotypes or
benefit from information on environment exposures? What advantages does
it offer for the investigation of new measures of environmental exposures
developed by the GEI exposure biology component?

Investigators: Are the investigators
appropriately trained and well suited to carry out this work? Is the work
proposed appropriate to the experience level of the principal investigator and
other researchers? Does the investigative team bring complementary and
integrated expertise to the project (if applicable)?

Environment: Does the scientific
environment in which the work will be done contribute to the probability of
success? Do the proposed studies benefit from unique features of the scientific
environment, or subject populations, or employ useful collaborative
arrangements? Is there evidence of institutional support?Is the bioinformatics
infrastructure sufficient to accomplish the goals of the project?

2.A. Additional Review
Criteria:

In addition to the above
criteria, the following items will continue to be considered in the
determination of scientific merit and the priority score:

Protection
of Human Subjects from Research Risk: The involvement of human subjects and protections from
research risk relating to their participation in the proposed research will be
assessed (see the Research Plan, Section E on Human Subjects in the PHS Form
398).

Inclusion
of Women, Minorities and Children in Research: The adequacy of plans to
include subjects from both genders, all racial and ethnic groups (and
subgroups), and children as appropriate for the scientific goals of the
research will be assessed.

2.B. Additional Review
Considerations

Budget: The reasonableness of the
proposed budget and the requested period of support in relation to the proposed
research. The priority score should not be affected by the evaluation of the
budget.

2.C. Sharing Research Data

The NIH has identified the GWA
component of GEI as a community resource project. As such, the program aims
to function openly by making all data available to the scientific community in
a timely manner prior to publication, with suitable restrictions for protection
of human research subjects. The applicant should provide specific plans
for data release in the application. It is expected that NIH will soon
establish a common data release policy for GWA studies and that all
participants will agree to abide by that policy; see Request for Information (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html).

Data
Sharing Plan: The reasonableness of the data sharing plan may be assessed by the
reviewers. However, reviewers will not factor the proposed data sharing plan
into the determination of scientific merit or the priority score. The presence
of a data sharing plan will be part of the terms and conditions of the award.
The funding organization will be responsible for monitoring the data sharing
policy. https://grants.nih.gov/grants/policy/data_sharing.

Program
staff will be responsible for the administrative review of the plan for sharing
data. The adequacy of the data sharing plan will be considered by program staff
of the funding organization when making recommendations about funding
applications. Program staff may negotiate modifications of the data sharing
plan with the awardee before recommending funding of an application. The final
negotiated version of the data sharing plan will become a condition of the
award of the cooperative agreement. The effectiveness of the data sharing will
be evaluated as part of the administrative review of each non-competing Grant
Progress Report (PHS 2590). See Section VI.3. Reporting.

Program staff will be
responsible for the administrative review of the plan for sharing research
resources.

The adequacy of the
resources sharing plan will be considered by Program staff of the funding
organization when making recommendations about funding applications. Program
staff may negotiate modifications of the data and resource sharing plans with
the awardee before recommending funding of an application. The final version of
the data and resource sharing plans negotiated by both will become a condition
of the award of the grant. The effectiveness of the resource sharing will be
evaluated as part of the administrative review of each non-competing Grant
Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

It is anticipated that
awards will be made by July 1, 2007.

Section
VI. Award Administration Information

1. Award Notices

After the peer review of
the application is completed, the PD/PI will be able to access his or her
Summary Statement (written critique) via the eRA Commons.

A formal notification in the form of a Notice
of Award (NoA) will be provided to the applicant organization. The NoA
signed by the grants management officer is the authorizing document. Once all
administrative and programmatic issues have been resolved, the NoA will be
generated via email notification from the awarding component to the grantee
business official (designated in item 12 on the Application Face Page). If a
grantee is not email enabled, a hard copy of the NoA will be mailed to the
business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Also Section
IV.5. Funding Restrictions.

2. Administrative and National
Policy Requirements

The NIH has identified the GWA
component of GEI as a community resource project. As such, the program aims
to function openly by making all data available to the scientific community in
a timely manner prior to publication, with suitable restrictions for protection
of human research subjects. It is expected that NIH will establish a common
data release policy for GWA studies prior to the anticipated award date for the
GEI-GWA Program, and that all awardees will agree to abide by that policy; see
Request for Information (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html).

The following Terms and
Conditions will be incorporated into the award statement and will be provided
to the Principal Investigator as well as to the appropriate institutional
official, at the time of award.

2.A. Cooperative Agreement
Terms and Conditions of Award

The following special
terms of award are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS grant administration regulations at 45 CFR Parts
74 and 92 (Part 92 is applicable when State and local Governments are eligible
to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for
this program will be the cooperative agreement (the NIH U01 Research Project Cooperative
Agreement award mechanism), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the NIH purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume
direction, prime responsibility, or a dominant role in the activities.
Consistent with this concept, the dominant role and prime responsibility
resides with the awardees for the project as a whole, although specific tasks
and activities may be shared among the awardees and the NIH as defined below.

2.A.1.
Principal Investigator Rights and Responsibilities

The
Principal Investigator will have the primary responsibility for defining the
details for the project within the guidelines of RFA HG-06-033 and for
performing the scientific activities. The Principal Investigator will
agree to accept close coordination, cooperation, and management of the project
as described under “NIH Responsibilities.” Specifically, the
Principal Investigator will:

Share DNA from an adequate number of samples in sufficient
quantity and quality for GWA or replication genotyping.

Share detailed phenotypic and environmental data, collected
according to widely-accepted and validated protocols, to NCBI and, as needed,
the GEI-GWA program’s Coordinating Center.

Provide high-quality documentation, including study
protocols, manuals, coding, and other information that will be sufficient for
outside users to understand and use the data with minimal assistance.

Share results according to the data sharing policy developed
for and by this program.

Participate in group activities, including a study-wide, GEI-GWA
Steering Committee to share design and analysis techniques and promote
comparability across genotyped studies wherever possible.

Not disclose confidential information obtained from other
members of the program.

Adhere to policies regarding data access, publication, and
intellectual property established by NIH and the GEI-GWA Steering Committee for
this program.

Adhere to NIH policies regarding genome-wide association
studies and other policies that might be established during the course of this
activity.

Submit periodic progress reports in a standard format, as
agreed upon by the GEI-GWA Steering Committee and Scientific Advisory Panel.

Attend GEI-GWA Steering Committee meetings and accept and
implement the common guidelines and procedures approved by the GEI-GWA Steering
Committee, Scientific Advisory Panel, and NIH.

Awardees
will retain custody of and have primary rights to the data and software
developed under these awards, subject to Government rights of access consistent
with current HHS, PHS, and NIH policies.

2.A.2. NIH
Responsibilities

An
NIH Project Scientist will have substantial programmatic involvement that is
above and beyond the normal stewardship role in awards, as described below.

The GEI-GWA
Project Scientist is a scientist of the NIH staff who will have substantial
scientific and programmatic involvement during the conduct of this activity
through technical assistance, advice, and coordination. However, the role
of NIH staff will be to facilitate and not to direct the activities. It
is anticipated that decisions in all activities will be reached by consensus of
the GEI-GWA program and that NIH staff will be given the opportunity to offer
input to this process. The GEI-GWA Project Scientist will participate as
a member of the GEI-GWA Steering Committee and will have one vote. The GEI-GWA
Project Scientist will have the following substantial involvement:

Participate with the other GEI-GWA
Steering Committee members in the group process of setting research priorities,
deciding optimal research approaches and protocol designs, and contributing to
the adjustment of research protocols or approaches as warranted. The GEI-GWA
Project Scientist will assist and facilitate the group process and not direct
it.

Make the assignment of genotyping
projects to the Genotyping Facilities.

Serve as a liaison, helping to
coordinate activities among and for the awardees, including acting as a liaison
to the NIH, and as an information resource for the awardees about genome
research activities. The GEI-GWA Project Scientist will also coordinate
the efforts of the GEI-GWA program with other groups conducting similar GWA
studies.

Attend all GEI-GWA Steering
Committee meetings as a voting member and assist in developing operating
guidelines, quality control procedures, and consistent policies for dealing
with recurrent situations that require coordinated action. The GEI-GWA Project
Scientist should be informed of all major interactions of members of the GEI-GWA
Steering Committee. The GEI-GWA Project Scientist will be responsible for
working with the GEI-GWA Coordinating Center to schedule the time and prepare
concise minutes or summaries of the GEI-GWA Steering Committee meetings, which
will be delivered to members of the group within 30 days after each meeting.

Report periodically on the
progress of the GEI-GWA Program to the Director, NHGRI and to the National
Advisory Council for Human Genome Research.

Retain the option to recommend the
withholding or reduction of support from any project that fails to achieve its
goals or comply with the Terms and Conditions of award.

Provide relevant expertise and
overall knowledge of NIH-sponsored research to facilitate the selection of
scientists not affiliated with the awardee institutions to serve on the
Scientific Advisory Panel.

Serve as a liaison between the GEI-GWA
Steering Committee and the Scientific Advisory Panel, attending Scientific Advisory
Panel meetings in a non-voting liaison member role.

Serve on subcommittees of the GEI-GWA
Steering Committee and the Scientific Advisory Panel, as appropriate.

Assist awardees in the
development, if needed, of policies for dealing with situations that require
coordinated action.

Provide advice in the management
and technical performance of the award.

Assist in promoting the
availability of the GEI-GWA data and related resources developed in the course
of this program to the scientific community at large.

Participate in data analyses,
interpretations, and, where warranted, co-authorship of the publication of
results of studies conducted through the GEI-GWA program.

An NHGRI Program
Director will be responsible for the normal scientific and programmatic
stewardship of the award and will be named in the award notice. The NHGRI
Program Director may also serve as the GEI-GWA Project Scientist.

If
reconsent is necessary, plans for reconsent, including consent forms, must be approved
by the NHGRI Program Director prior to implementation.

The
Program Director may withhold or reduce support from any Study Investigator
that fails to achieve its goals or comply with the Terms and Conditions of
Award.

Other NIH
staff may assist the awardees as designated by the Project Scientist and
Program Director.

An
NIH-wide GEI Coordinating Committee, administratively led by the National Human
Genome Research Institute (NHGRI) and the National Institute of Environmental
Health Sciences (NIEHS) will participate in the selection of awardees, oversee
the complex set of GEI programs, including the GEI-GWA program, and ensure
coordination of GEI throughout the NIH.

The NCBI
is substantially involved. Prior to making awards, they will provide
technical evaluation of the meta-data and, when appropriate, individual-level
data that are shared by applicants for Study Investigators
(RFA-HG-06-033). NCBI will manage and maintain security for the GEI-GWA
database. They will work with the Genotyping Facilities, the Coordinating Center, and Study Investigators, as appropriate, to ensure data integrity and
clarify data definitions.

2.A.3. Collaborative
Responsibilities

The Genes
and Environment Initiative (GEI) is a four-year, NIH-wide program. GEI is
intended to be a multi-component program involving several related
solicitations. A major component will support genome-wide association
studies (GWAS), either in an initial discovery phase (assaying single
nucleotide polymorphisms, or SNPs, to capture at least 80% of human genomic
variation), or in a replication phase (assaying a subset of the most strongly
associated SNPs or other genetic variants in one or more additional groups of
subjects), or both. Other GEI genetics components under consideration for
future solicitations include development of data analytic methods, further
replication and fine mapping studies, sequencing, functional studies, database
development, and clinical translation. This RFA (HG-06-033) for Study
Investigators, in concert with RFA-HG-06-032 for a Coordinating Center and RFA-HG-06-014 for Genotyping Facilities, comprise the GWA component of GEI
(GEI-GWA).

Close
interaction among the participating investigators will be required, as well as
significant involvement from the NIH, to develop appropriate strategies and
tools to design, perform, and analyze genome-wide association studies. The awardees
from all three GEI-GWA RFAs and the GEI-GWA Project Scientist will meet as the
GEI-GWA Steering Committee three times per year and monthly on conference calls
as needed to share information on data resources, methodologies, analytical
tools, as well as data and preliminary results. Key co-investigators and
pre- and postdoctoral trainees, especially those who are members of
under-represented minority groups or those from different but related
disciplines, in addition to the PIs, are eligible to attend these meetings.

The GEI-GWA
Steering Committee will serve as the main governing board of the GEI-GWA program.
The GEI-GWA Steering Committee will be responsible for coordinating the
activities being conducted by the GEI-GWA program. The GEI-GWA Steering Committee
membership will include one GEI-GWA Project Scientist and the P.I. from each
awarded cooperative agreement. The awardees funded through the concurrent
RFAs, HG-06-032, “Genome-wide Association Studies in the Genes and
Environment Initiative – Coordinating Center,” which will support
the coordination and analytic needs of this program, and HG-06-014, “Genome-wide
Association Studies in the Genes and Environment Initiative – Genotyping
Facilities,” which will support the genotyping needs of this program, will
also participate in the program and be members of the GEI-GWA Steering
Committee. The GEI-GWA Steering Committee may add additional members, and
other government staff may attend the GEI-GWA Steering Committee meetings as
desired. It is anticipated that additional coordination mechanisms will
be set up with other U.S. and international groups that may collaborate with the
GEI-GWA program.

To
address particular issues, the GEI-GWA Steering Committee may establish working
groups as needed, which will include representatives from the program and the NIH
and possibly other experts. These might include groups to: 1) assess and
enhance standardization and comparability of phenotypic and exposure variables
across studies undergoing GEI-GWA genotyping; 2) address data management
issues; 3) propose and evaluate strategies for follow-up of GEI-GWA discovery
and replication findings; 4) develop quality standards and methods to assess
data quality; and 5) handle communication issues and develop principles for
reporting findings.

All unidentified
phenotypic, environmental exposure, and genotypic data proposed for GEI-GWA
analysis in individual research subjects will be made available to the
scientific community through a controlled access process managed by NIH. Summary
data and other non-identifying information such as study protocols,
descriptions, and publications will be made openly available through a public
web site and publication in the scientific literature.

Awardees
agree to:

Share phenotypic and exposure data
on individual research subjects along with high-quality documentation,
protocols, manuals, etc to facilitate use by investigators unfamiliar with the
study.

Participate in the GEI-GWA Steering
Committee meetings (expected to occur three times per year in the Bethesda, MD area) and regular telephone conference calls.

Cooperate with other awardees in
the development and design of research methods, protocols, tools, and
strategies.

Abide by common definitions,
protocols, procedures, etc. as chosen by majority vote of the GEI-GWA Steering
Committee.

Actively seek to exchange
analytical methods and potentially data sets with other awardees in the GEI-GWA
Program.

Accept and comply with study
policies established by NIH, and with additional non-conflicting policies approved
by the GEI-GWA Steering Committee.

Cooperate with other awardees in
the publication and dissemination of GEI-GWA Program results and the eventual
release to the scientific community of methods, tools, and results, and other
resources.

A Scientific
Advisory Panel (SAP) will be established by the NIH to evaluate the progress of
the GEI-GWA program. The SAP will provide recommendations to the Director of
NHGRI, the National Advisory Council for Human Genome Research, and the NIH GEI
Coordinating Committee about the progress and scientific direction of all
components of the GEI-GWA program. The SAP will be composed of six to
eight senior scientists with relevant expertise, although the membership may be
enlarged permanently or on an ad hoc basis as needed.

The SAP
will meet at least twice a year; some meetings may be conducted by telephone
conference. At least once a year, there will be a joint meeting with the GEI-GWA
Steering Committee to allow the members of the both the SAP and the GEI-GWA
Steering Committee to interact directly. Twice a year the SAP will make
recommendations regarding progress of the GEI-GWA program and present advice to
the Director of NHGRI, the National Advisory Council for Human Genome Research,
and the NIH GEI Coordinating Committee about changes, if any, which may be
necessary in the GEI-GWA program.

2.A.4.
Arbitration Process

Any disagreements that
may arise in scientific or programmatic matters (within the scope of the award)
between award recipients and the NIH may be brought to arbitration. An
Arbitration Panel composed of three members will be convened. It will have
three members: a designee of the Steering Committee chosen without NIH staff
voting, one NIH designee, and a third designee with expertise in the relevant
area who is chosen by the other two; in the case of individual disagreement,
the first member may be chosen by the individual awardee. This special
arbitration procedure in no way affects the awardee's right to appeal an
adverse action that is otherwise appealable in accordance with PHS regulations
42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to
submit electronically quarterly reports that describe the data and specimens that
have been shared with the designated Genotyping Facility and NCBI database(s),
respectively. The quarterly report will be used as a management tool for
the NIH and the GEI-GWA Steering Committee to determine the most efficient
approaches to conducting studies and to identify early any correctable
problems. Reporting on cost will also be required.

We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research, peer review, and financial or grants
management issues:

Human Subjects
Protection:Federal regulations
(45CFR46) require that applications and proposals involving human subjects must
be evaluated with reference to the risks to the subjects, the adequacy of
protection against these risks, the potential benefits of the research to the
subjects and others, and the importance of the knowledge gained or to be gained
(http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Sharing
Research Data:Investigators submitting
an NIH application seeking $500,000 or more in direct costs in any single year
are expected to include a plan for data sharing or state why this is not
possible (https://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their
institutions, on issues related to institutional policies and local IRB rules,
as well as local, State and Federal laws and regulations, including the Privacy
Rule. Reviewers will consider the data sharing plan but will not factor the
plan into the determination of the scientific merit or the priority score.

Access to Research
Data through the Freedom of Information Act:The Office of Management
and Budget (OMB) Circular A-110 has been revised to provide access to research
data through the Freedom of Information Act (FOIA) under some circumstances.
Data that are (1) first produced in a project that is supported in whole or in
part with Federal funds and (2) cited publicly and officially by a Federal
agency in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for applicants to
understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Inclusion of
Women And Minorities in Clinical Research:It is the policy of the
NIH that women and members of minority groups and their sub-populations must be
included in all NIH-supported clinical research projects unless a clear and
compelling justification is provided indicating that inclusion is inappropriate
with respect to the health of the subjects or the purpose of the research. This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43). All investigators proposing clinical research should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children
as Participants in Clinical Research:The NIH maintains a
policy that children (i.e., individuals under the age of 21) must be included
in all clinical research, conducted or supported by the NIH, unless there are
scientific and ethical reasons not to include them.

Required Education on
the Protection of Human Subject Participants:NIH policy requires
education on the protection of human subject participants for all investigators
submitting NIH applications for research involving human subjects and
individuals designated as key personnel. The policy is available at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

NIH Public
Access Policy:NIH-funded investigators
are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central
(PMC) an electronic version of the author's final manuscript upon acceptance
for publication, resulting from research supported in whole or in part with
direct costs from NIH. The author's final manuscript is defined as the final
version accepted for journal publication, and includes all modifications from
the publishing peer review process.

NIH is requesting that
authors submit manuscripts resulting from 1) currently funded NIH research
projects or 2) previously supported NIH research projects if they are accepted
for publication on or after May 2, 2005. The NIH Public Access Policy applies
to all research grant and career development award mechanisms, cooperative
agreements, contracts, Institutional and Individual Ruth L. Kirschstein
National Research Service Awards, as well as NIH intramural research studies.
The Policy applies to peer-reviewed, original research publications that have
been supported in whole or in part with direct costs from NIH, but it does not
apply to book chapters, editorials, reviews, or conference proceedings.
Publications resulting from non-NIH-supported research projects should not be
submitted.

Standards for Privacy
of Individually Identifiable Health Information:The Department of Health
and Human Services (DHHS) issued final modification to the "Standards for
Privacy of Individually Identifiable Health Information", the
"Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal
regulation under the Health Insurance Portability and Accountability Act
(HIPAA) of 1996 that governs the protection of individually identifiable health
information, and is administered and enforced by the DHHS Office for Civil
Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant
Applications or Appendices:
All applications and proposals
for NIH funding must be self-contained within specified page limitations. For
publications listed in the appendix and/or Progress report, internet addresses
(URLs) must be used for publicly accessible on-line journal
articles. Unless otherwise specified in this solicitation,
Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation
to view the Internet sites. Furthermore, we caution reviewers that their
anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:The Public Health
Service (PHS) is committed to achieving the health promotion and disease
prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This PA is related to one or more of the
priority areas. Potential applicants may obtain a copy of "Healthy People
2010" at http://www.health.gov/healthypeople.

Authority and
Regulations:This program is described in
the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review. Awards are made under the
authorization of Sections 301 and 405 of the Public Health Service Act as
amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR
Parts 74 and 92. All awards are subject to the terms and conditions, cost
principles, and other considerations described in the NIH Grants Policy Statement. The
NIH Grants Policy Statement can be found at https://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly
encourages all grant recipients to provide a smoke-free workplace and
discourage the use of all tobacco products. In addition, Public Law 103-227,
the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in
some cases, any portion of a facility) in which regular or routine education,
library, day care, health care, or early childhood development services are
provided to children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

Loan Repayment
Programs:NIH encourages
applications for educational loan repayment from qualified health professionals
who have made a commitment to pursue a research career involving clinical,
pediatric, contraception, infertility, and health disparities related areas.
The LRP is an important component of NIH's efforts to recruit and retain the
next generation of researchers by providing the means for developing a research
career unfettered by the burden of student loan debt. Note that an NIH grant is
not required for eligibility and concurrent career award and LRP applications
are encouraged. The periods of career award and LRP award may overlap providing
the LRP recipient with the required commitment of time and effort, as LRP
awardees must commit at least 50% of their time (at least 20 hours per week
based on a 40 hour week) for two years to the research. For further information,
please see: http://www.lrp.nih.gov.